Seasonal breeding is a common reproductive strategy among vertebrate species and is a natural process that enables the young to be raised during periods of greatest survivability. Seasonal breeding is characterized by recurring annual periods of fertility and infertility that are a result of a natural endogenous physiological mechanism. Environmental factors such as photoperiod, temperature and nutrition may slightly modify this mechanism, particularly in the respect that they help maintain appropriate timing of reproductive events during the year.
The endogenous physiological nature of seasonal breeding can be illustrated by an example. Many species of birds, including domestic turkeys and some species of chickens become fertile and breed in the spring under the stimulatory influence of long daylengths. However, in summer, even though daylengths are still long, reproductive activity declines and the birds become infertile. This is a natural mechanism preventing birth of young too late in the year to preclude winter survival. The mechanism for the summer decline in fertility is endogenous in that these birds are no longer responsive to the stimulatory influences of long daylengths as they had been in spring. Some other economically important seasonal breeders include: sheep, mink, goats and deer, naturally fertile in fall under the influence of short daylengths then becoming spontaneously infertile in mid-late winter.
Furthermore, the reproductive system of Syrian hamsters is inhibited by short daylengths in fall but not in late winter and early spring. The basis for sensitivity and refractoriness to daylengths is unknown but probably involves the neuroendocrine system.
Resetting the endogenous seasonal mechanism would have clear economic benefits by increasing the numbers of animals that could be produced.
Applicants' laboratory has been researching seasonality in fish, birds and mammals for over 20 years. This research suggested that mechanisms controlling the seasonality are similar in all vertebrate animals and involves changes in brain neurotransmitter activities.
Recently, Meier and Wilson (the inventors) discovered that L-dihydroxyphenylalanine (L-DOPA) has a vital role in seasonality. L-DOPA was found to be present in hypothalamic areas of the brain (anterior hypothalamic nuclei) that regulate reproductive activity in much higher concentrations in reproductively stimulated than in reproductively regressed hamsters. Blood concentrations of L-DOPA were also greater in reproductively active hamsters than in the inactive animals. Plasma L-DOPA concentrations in reproductively inactive hamsters have been found to be about 0.62 ug/ml, while the level in reproductively active hamsters is in the range of 0.85 to 1.09 ug/ml.
It has been observed that 40-50% of an oral dose of L-DOPA (25 mg/kg, dog) is absorbed from the digestive tract (Aminoff, 1987). However, the absorption of L-DOPA is highly dependent upon the frequency of gastric emptying, the protein content of the diet and whether taken with a meal (Nutt et al., 1987). Peak plasma concentrations of L-DOPA are attained within 1-2 hours. After 8 hours, 66% of an oral dose of L-DOPA can be recovered in the urine as homovanillic acid and dihydroxyphenylacetic acid (Aminoff, 1987). The half-life of L-DOPA in the blood stream is 1-3 hours (Gilman et al., 1985).
Instead of an oral dose, L-DOPA may be administered by time release subcutaneous implant or by injection, both of which are approximately three times more efficient than an oral dose.
L-DOPA, a catecholamine precursor, has been used for treatment of degenerative conditions brought on by old age. For years L-DOPA has been used to treat Parkinson's disease, a disease of later life characterized by rhythmic tremors and muscular rigidity caused by degeneration of the basal ganglia of the brain. Additionally, treatment with L-DOPA has been found to enhance response to estrogen feedback and maintain estrous cycles in old female rats in various stages of reproductive decline (Forman et al., 1980). Furthermore, in U.S. Pat. No. 4,241,082, Baba et al. teach the use of L-DOPA for promoting the reproductive ability in domestic animals suffering from reproductive disorders during their breeding season. It does not suggest that L-DOPA can be used to stimulate the reproduction of seasonally reproductively inactive animals, which is not a disorder. It is merely part of the normal breeding cycle of the animal.
The present invention is based on the hypothesis that the high levels of L-DOPA in the blood and brain have a causal role in establishing and maintaining reproductive readiness.
There is presently no method known to applicants that compares with the present invention for producing reproductive activity in animals during a normally non-reproductive season of the year, which is not brought on by any disorder. Present methodology involves artificial manipulation of the daily photoperiod or injections of reproductive hormones. For example, short daylengths in summer can cause premature breeding in sheep that otherwise occurs during the fall (Jainudeen and Hafez, 1987). Recently, melatonin, a pineal gland hormone produced in greater amounts during short daylength exposure, has been employed to initiate early breeding. (Roche et al., 1985; Ward and Williams, 1987). Artificially lengthening the daylength at the end of the seasonal anestrous period in mares may initiate early estrous cycling (Allen, 1978). These methods are expensive and while they produce young at a different season, they do not increase the total number that can be produced during a year. Injections of reproductive hormones, such as gonadotropin releasing hormone and progestogens, have also been used to develop reproductive readiness in several vertebrate animals, such as sheep, horses, swine, and poultry (Robinson et al., 1975; McGlothlin et al., 1979; Haresign, et al., 1983). This method is labor intensive and uneconomical or unfeasible in most instances.
The following is a list of the relevant prior art references cited herein:
Allen, W. R. 1978. Control of estrous and ovulation in the mare. In: Control of Ovulation (D. B. Crighton, G. R. Foxcroft, N. B. Haynes, G. E. Lamming, eds.), Butterworths, London.
Aminoff, M. J. 1987. Pharmacological management of Parkinsonism and other movement disorders. In: Basic and Clinical Pharmacology (B. G. Katzung, ed.), Appleton and Lange, Norwolk, Ct. pp. 306-309.
Forman, L. J., W. E. Sonntag, N. Miki, and J. Meites 1980. Maintenance by L-DOPA treatment of estrous cycles and LH response to estrogen in aging female rats. Exp. Aging Res. 6:547.
Gaston, S. and M. Menaker 1967. Photoperiodic control of hamster testis. Science 158:925.
Gilman, A. G., L. Goodman and A1 Gilman 1985. Pharmacological Basis of Therapeutics. 7th Ed., MacMillan Publ., N.Y.
Haresign, W., B. J. McLoed and G. M. Webster 1983. Endocrine control of reproduction in the ewe. In: Sheep Production (W. Haresign, ed.). Butterworth, London. pp. 353-379.
Jainudeen, M. R. and E. S. E. Hafez 1987 (Reproductive cycles of sheep and goats. In: Reproduction in Farm Animals (E. S. E. Hafez, ed.), 5th ed., Lea and Febiger, Philadelphia. pp. 315-323.
McGlothlin, D. E., E. L. Squires, W. B. Stevens and B. W. Pickett 1979. Effect of an oral progestin on the estrous cycle and fertility in mares. J. Anim. Sci. 4:729.
Nutt, J. G., W. R. Woodward, J. P. Hammerstal, J. H. Carter and J. L. Anderson 1987. The on-off phenomenon in Parkinson's disease: Relation to levodopa absorption and transport. New Engl. J. Med. 310:483.
Reiter, R. J. 1973. Pineal control of the seasonal reproductive rhythm in male golden hamsters exposed to natural daylengths and temperature. Endocrinology 92:423.
Reiter, R. J. 1981. The pineal and its hormones in the control of reproduction in mammals. Endocrine Rev. 1:109.
Robinson, J. E. and B. K. Follett 1982. Photoperiodism in Japanese quail: The termination of seasonal breeding by photorefractoriness. Proc. R. Soc. London, Ser. B. 215:95.
Robinson, J. J., C. Fraser and I. McHatter 1975. Use of progestogens and photoperiodism in improving the reproductive rate of the ewe. Ann. Biol. Anim. Biochem. Biophys. 15:345.
Roche, J. F., J.P. Hanrahan, J. F. Quicke and E. Ramayne 1985. Effect of melatonin on time of onset of breeding season in different breeds of sheep. In: Endocrine Causes of Seasonal and Lactational Anestrous in Farm Animals (F. Ellendorf, ed.), Martinus Nijhoff, Dordrecht, pp. 55-64.
Rusak, B. and L. P. Morin 1967. Testicular responses to photoperiod are blocked by lesions of the suprachiasmatic nuclei of golden hamsters. Biol. Reprod. 15:366.
Siopes, T. D. and W. O. Wilson 1975. The cloacal gland: An external indication of testicular development in Coturnix. Poult. Sci. 54:1225.
Stetson, M. H., M. Watson-Whitmyre and K. S. Matt. 1977. Termination of photorefractoriness in the golden hamster: Photoperiodic requirements. J. Exp. Zool. 202:81.
Ward, S. J. and H. L. Williams 1987. Out-of-season breeding in adult Suffolk ewes following light and melatonin treatment. In: British Society of Animal Production. Winter Meeting, 23-24 Mar. 1987. Program and Summaries, Paper No. 88.
U.S. Pat. No. 4,241,082 issued on Dec. 23, 1980 to Yoshihiko Baba and Hiroyoshi Horikoshi, entitled "Agents for Promoting Reproductive Ability of Domestic Animals."
Therefore, one object of the invention is to provide a process to alter seasonality in seasonal breeding vertebrates.
Another object of this invention is to provide a process to convert vertebrates from a reproductively inactive to a reproductively active state.
Another object of this invention is to provide a process to maintain vertebrates in a reproductively active state during photoperiodic conditions which would otherwise cause inhibition of reproductive activity.
Another object of this invention is to provide a process to shift seasonality which is safe and easy to administer.
Another object of this invention is to use the prevailing photoperiodic conditions to stimulate reproductive activity.
Still another object of this invention is to provide a process to inhibit the depletion of L-DOPA in a vertebrate's bloodstream.